Alternative titles; symbols
ORPHA: 75249; DO: 0111425, 397;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.42 | Cardiomyopathy, familial restrictive, 1 | 115210 | Autosomal dominant | 3 | TNNI3 | 191044 |
A number sign (#) is used with this entry because of evidence that familial restrictive cardiomyopathy-1 (RCM1) is caused by heterozygous mutation in the gene encoding the cardiac muscle isoform of troponin I (TNNI3; 191044) on chromosome 19q13.
Restrictive cardiomyopathy (RCM) is a myocardial disease characterized by impaired ventricular filling and reduced diastolic volume in the presence of normal systolic function and normal or near-normal myocardial thickness. The disease is characterized by symptoms of progressive left- and right-sided heart failure. The overall prognosis is poor, especially when onset is in childhood, and patients often require cardiac transplantation (Mogensen et al., 2003).
Genetic Heterogeneity of Familial Restrictive Cardiomyopathy
Other forms of familial restrictive cardiomyopathy include RCM2 (609578), mapped to chromosome 10q23; RCM3 (612422), caused by mutation in the TNNT2 gene (191045) on chromosome 1q32; RCM4 (see 615248), caused by mutation in the MYPN gene (608517) on chromosome 10q21; RCM5 (see 617047), caused by mutation in the FLNC gene (102565) on chromosome 7q32; and RCM6 (619433), caused by mutation in the KIF20A gene (605664) on chromosome 5q31.
Aroney et al. (1988) described father and daughter with idiopathic restrictive cardiomyopathy. The hemodynamic profile was characteristic, and there was echocardiographic evidence of diastolic dysfunction and atrial enlargement without ventricular dilatation.
Kushwaha et al. (1997) reviewed the evidence for a familial basis of idiopathic restrictive cardiomyopathy. Fitzpatrick et al. (1990) reported an Italian family in which autosomal dominant restrictive cardiomyopathy with atrial ventricular block and skeletal myopathy occurred in members of 5 generations. Symptoms developed in the third to fourth decade of life, with the eventual appearance of atrial ventricular block and skeletal muscle weakness. Katritsis et al. (1991) and Ishiwata et al. (1993) likewise described familial restrictive cardiomyopathy associated with distal skeletal myopathy. Feld and Caspi (1992) described familial cardiomyopathy with variable hypertrophic (see 192600) and restrictive features. A familial nonhypertrophic restrictive cardiomyopathy with autosomal dominant inheritance and incomplete penetrance was described by Cooke et al. (1994) in association with Noonan syndrome (163950).
Chen et al. (2001) reviewed the clinical spectrum of restrictive cardiomyopathy in 14 children, 7 of whom had familial cardiomyopathy. The patients were diagnosed from age 4 months to 17.3 years (mean, 7.8 years); presenting symptoms included dyspnea, pneumonia, syncope, ascites, inability to walk, and heart murmur, and some were screened due to positive family history. On electrocardiogram there was biatrial enlargement without significant dysrhythmia; chest x-ray showed cardiomegaly with pulmonary congestion, and 2 patients had pulmonary edema. Echocardiogram revealed marked dilation of the left atrium with normal-sized left ventricle (LV) and normal LV shortening fraction. Six patients had mid-septal bulging with an hourglass appearance of the LV on 4-chamber view, and 3 patients had mild apical LV hypertrophy. There was increased early diastolic filling and decreased atrial filling velocity by Doppler; reversal of pulmonary vein A-waves was common. Endomyocardial biopsy was performed in 11 patients and showed fibrosis with myocardial hypertrophy of various degrees in 7 patients, myofiber hypertrophy with increased number of mitochondria in 2, endocardial fibroelastosis in 1, and fibrosis with myocardial degeneration in 1 patient with eosinophilia. Autopsy in 1 patient showed mitochondrial abnormality with foamy myocardial transformation. Skeletal muscle biopsy was performed in 8 patients, but none had specific diagnostic findings. The clinical course was variable, although the majority of patients deteriorated rapidly: 5 patients died 1 week to 1.3 years after presentation (mean, 13.2 months), but 2 patients remained well for 8.3 and 9.1 years.
The transmission pattern of RCM1 in the families reported by Mogensen et al. (2003) was consistent with autosomal dominant inheritance. Some of the mutations occurred de novo.
Mogensen et al. (2003) studied a large family in which individuals were affected by either idiopathic restrictive cardiomyopathy or hypertrophic cardiomyopathy. Linkage analysis to selected sarcomeric contractile protein genes identified TNNI3 as a likely disease gene. Mutation analysis revealed a novel missense mutation that cosegregated with the disease in the family (191044.0005). Mogensen et al. (2003) investigated an additional 9 unrelated RCM patients with restrictive filling patterns, biallelic dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in 6 of these 9 patients (see 191044.0006-191044.0008). Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene.
Aroney, C., Bett, N., Radford, D. Familial restrictive cardiomyopathy. Aust. New Zeal. J. Med. 18: 877-878, 1988. [PubMed: 2977941] [Full Text: https://doi.org/10.1111/j.1445-5994.1988.tb01654.x]
Chen, S., Balfour, I. C., Jureidini, S. Clinical spectrum of restrictive cardiomyopathy in children. J. Heart Lung Transplant. 20: 90-92, 2001. [PubMed: 11166616] [Full Text: https://doi.org/10.1016/s1053-2498(00)00162-5]
Cooke, R. A., Chambers, J. B., Curry, P. V. Noonan's cardiomyopathy: a non-hypertrophic variant. Brit. Heart J. 71: 561-565, 1994. [PubMed: 8043339] [Full Text: https://doi.org/10.1136/hrt.71.6.561]
Feld, S., Caspi, A. Familial cardiomyopathy with variable hypertrophic and restrictive features and common HLA haplotype. Isr. J. Med. Sci. 28: 277-280, 1992. [PubMed: 1597356]
Fitzpatrick, A. P., Shapiro, L. M., Rickards, A. F., Poole-Wilson, P. A. Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy. Brit. Heart J. 63: 114-118, 1990. [PubMed: 2317404] [Full Text: https://doi.org/10.1136/hrt.63.2.114]
Ishiwata, S., Nishiyama, S., Seki, A., Kojima, S. Restrictive cardiomyopathy with complete atrioventricular block and distal myopathy with rimmed vacuoles. Jpn. Circ. J. 57: 928-933, 1993. [PubMed: 8371486] [Full Text: https://doi.org/10.1253/jcj.57.928]
Katritsis, D., Wilmshurst, P. T., Wendon, J. A., Davies, M. J., Webb-Peploe, M. M. Primary restrictive cardiomyopathy: clinical and pathologic characteristics. J. Am. Coll. Cardiol. 18: 1230-1235, 1991. [PubMed: 1918700] [Full Text: https://doi.org/10.1016/0735-1097(91)90540-p]
Kushwaha, S. S., Fallon, J. T., Fuster, V. Restrictive cardiomyopathy. New Eng. J. Med. 336: 267-276, 1997. [PubMed: 8995091] [Full Text: https://doi.org/10.1056/NEJM199701233360407]
Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003. [PubMed: 12531876] [Full Text: https://doi.org/10.1172/JCI16336]